Is there a genetic path to despair repair?

The difference between resilience and depression may have roots deep in brain cells, a study found. (Kristian Sekulic / Getty Images)

The clues to what makes one person cope with social stress and another fall into a funk might be encrypted in some very, very tiny print deep in the nucleus of brain cells.

At least, that is, in mice.

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Juicing up a tiny forebrain region of mice with a protein involved in cell signaling protected rodents from developing symptoms of social avoidance, helped them be less anxious when running mazes, and made them less prone to just giving up when forced to swim, according to a study published online Wednesday in the journal Nature.

"The scientific term is behavioral despair," said neuroscientist Caroline Dias of the Icahn School of Medicine at Mount Sinai, lead author of the study. "It's a measure of depression in mice. You can argue, how do we really know what the mice are thinking, but the nice thing about that model is that it responds to anti-depressants."

Those tests, however, were just the start. Dias' team chemically traced the behavioral effects down to sub-cellular roots, and found what could be a promising new path to tackling depression by focusing on the health of neurons.

Such an approach would be good news for those suffering from depression, because currently popular drug treatments have far broader targets — the chemical transmitters that flow across the gap between neurons — and can have troubling side effects. They also don't work well for as much as a third of patients.

"What we're showing is that there is a spectrum of healthiness in these neurons and I think that we identified one pathway that's particularly important in promoting resilience by promoting their health," Dias said.

The researchers have been exploring cell-level activity in the nucleus accumbens, a tiny part of the forebrain involved in reward circuitry. Mice have one, and so do humans.

Three years ago, the researchers reported some oddities in gene regulation in neurons in that region, and these were associated with "social defeat" behavior among mice bullied by more dominant males.

The researchers set out to trace this signaling path. That led them downstream a bit, to a protein called beta catenin. Levels of the protein have been linked to psychiatric disorders, including depression.

In more resilient mice, beta catenin gets inside the nucleus of spiny neurons and kick-starts a gene known as Dicer1. That leads to a cascade of events that tilts a molecular battlefield toward resilience proteins. A key part appears to involve tiny strands of RNA, according to the study.

These tiny micro-RNA strands, which look somewhat like half a ladder, often "turn off" genes.

That's when things get both interesting and a bit more gray, according to Gerhard Schratt, a microbiologist at the University of Marburg, Germany, who wrote an accompanying analysis of the study. He called the link between beta catenin and micro RNA "perhaps the most exciting aspect" of the study.

But, he noted, only a few micro-RNA were strongly linked to beta catenin's effect on this gene, which could imply that there are a bunch of unexplored pathways that don't involve the protein. Plus, there are close to 1,000 micro-RNA linked to beta catenin's activity, making the prospect of identifying the relevant one "a long shot," Schratt wrote.

The researchers will test the odds and try to sort out which of these micro-RNA matter most. Any breakthrough that narrows the potential target of future drugs will be a "step in the right direction," Dias said.

"Perhaps there are other ways that we can address anti-depressant development that go beyond the scope of just the neurotransmitters that are being released in the synaptic cleft, and actually get to the health of the neuron itself," she said.